keyword
https://read.qxmd.com/read/35873773/exome-sequencing-of-a-portuguese-cohort-of-frontotemporal-dementia-patients-looking-into-the-als-ftd-continuum
#21
JOURNAL ARTICLE
Miguel Tábuas-Pereira, Isabel Santana, Elizabeth Gibbons, Kimberly Paquette, Maria Rosário Almeida, Inês Baldeiras, Jose Bras, Rita Guerreiro
Introduction: Frontotemporal dementia (FTD) is considered to be part of a continuum with amyotrophic lateral sclerosis (ALS). Many genes are associated with both ALS and FTD. Yet, many genes associated with ALS have not been shown to cause FTD. We aimed to study a Portuguese cohort of FTD patients, searching for variants in genes associated with both FTD and/or ALS. Methods: We included 57 thoroughly characterized index FTD patients from our memory clinic, who were not carriers of pathogenic variants in GRN, MAPT or C9orf72 ...
2022: Frontiers in Neurology
https://read.qxmd.com/read/35845111/frustration-analysis-of-tbk1-missense-mutations-reported-in-als-ftd-and-cancer-patients
#22
JOURNAL ARTICLE
Fatima Khatoon, Vijay Kumar, Farah Anjum, Alaa Shafie, Mohd Adnan, Md Imtaiyaz Hassan
Tank-binding kinase 1 (TBK1) is a multifunctional kinase having essential roles in cellular processes, autophagy/mitophagy, and selective clearance of damaged proteins. More than 90 mutations in the TBK1 gene are linked with multiple cancer types, amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD). Some of these missense mutations disrupt the abilities of TBK1 to dimerize, associate with the mitophagy receptor optineurin (OPTN), autoactivate, or catalyze phosphorylation. Some mutations may cause severe dysregulation of the pathway, while others induce a limited disruption...
August 2022: 3 Biotech
https://read.qxmd.com/read/35743272/optineurin-deficiency-and-insufficiency-lead-to-higher-microglial-tdp-43-protein-levels
#23
JOURNAL ARTICLE
Nikolina Prtenjaca, Matea Rob, Muhammad S Alam, Andrea Markovinovic, Cristiana Stuani, Emanuele Buratti, Ivana Munitic
Mutations in optineurin, a ubiquitin-binding adaptor protein, cause amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease of motor neurons linked to chronic inflammation and protein aggregation. The majority of ALS patients, including those carrying the optineurin mutations, exhibit cytoplasmic mislocalization, ubiquitination, and aggregation of nuclear TAR DNA-binding protein 43 kDa (TDP-43). To address the crosstalk between optineurin and TDP-43, we generated optineurin knockout (KO) neuronal and microglial cell lines using the CRISPR/Cas9 approach...
June 19, 2022: International Journal of Molecular Sciences
https://read.qxmd.com/read/35666053/targeted-copy-number-variant-identification-across-the-neurodegenerative-disease-spectrum
#24
JOURNAL ARTICLE
Allison A Dilliott, Kristina K Zhang, Jian Wang, Agessandro Abrahao, Malcolm A Binns, Sandra E Black, Michael Borrie, Dar Dowlatshahi, Elizabeth Finger, Corinne E Fischer, Andrew Frank, Morris Freedman, David Grimes, Ayman Hassan, Mandar Jog, Sanjeev Kumar, Anthony E Lang, Jennifer Mandzia, Mario Masellis, Stephen H Pasternak, Bruce G Pollock, Tarek K Rajji, Ekaterina Rogaeva, Demetrios J Sahlas, Gustavo Saposnik, Christine Sato, Dallas Seitz, Christen Shoesmith, Thomas D L Steeves, Richard H Swartz, Brian Tan, David F Tang-Wai, Maria C Tartaglia, John Turnbull, Lorne Zinman, Robert A Hegele
BACKGROUND: Although genetic factors are known to contribute to neurodegenerative disease susceptibility, there remains a large amount of heritability unaccounted for across the diagnoses. Copy number variants (CNVs) contribute to these phenotypes, but their presence and influence on disease state remains relatively understudied. METHODS: Here, we applied a depth of coverage approach to detect CNVs in 80 genes previously associated with neurodegenerative disease within participants of the Ontario Neurodegenerative Disease Research Initiative (n = 519)...
August 2022: Molecular Genetics & Genomic Medicine
https://read.qxmd.com/read/35661277/optn-variants-in-als-cases-a-case-report-of-a-novel-mutation-and-literature-review
#25
REVIEW
Yan Mou, Min Li, Mengling Liu, Jia Wang, Guofeng Zhu, Yunhong Zha
INTRODUCTION: Optineurin (OPTN)-associated mutations have been implicated in the development of type 12 amyotrophic lateral sclerosis (ALS12). We reported a case of ALS with a new OPTN variant (p.D527fs) and reviewed relevant literature to better understand the phenotypes and pathophysiological mechanisms of ALS12. METHODS: We report a case of a 55-year-old female patient with a new heterozygous variant of the OPTN gene. A literature search of ALS cases associated with the OPTN gene mutations was performed in PubMed with the search criteria as [("amyotrophic lateral sclerosis") OR ("motor neuron disease")] AND ("OPTN")...
September 2022: Neurological Sciences
https://read.qxmd.com/read/35143975/modeling-seeding-and-neuroanatomic-spread-of-pathology-in-amyotrophic-lateral-sclerosis
#26
JOURNAL ARTICLE
Sneha Pandya, Pedro D Maia, Benjamin Freeze, Ricarda A L Menke, Kevin Talbot, Martin R Turner, Ashish Raj
The neurodegenerative disorder amyotrophic lateral sclerosis (ALS) is characterized by the progressive loss of upper and lower motor neurons, with pathological involvement of cerebral motor and extra-motor areas in a clinicopathological spectrum with frontotemporal dementia (FTD). A key unresolved issue is how the non-random distribution of pathology in ALS reflects differential network vulnerability, including molecular factors such as regional gene expression, or preferential spread of pathology via anatomical connections...
May 1, 2022: NeuroImage
https://read.qxmd.com/read/34844057/knockdown-of-optineurin-controls-c2c12-myoblast-differentiation-via-regulating-myogenin-and-myod-expressions
#27
JOURNAL ARTICLE
Kenichi Ishikawa, Mutsuko Araki, Yoshito Nagano, Atsuko Motoda, Takeo Shishido, Takashi Kurashige, Tetsuya Takahashi, Hiroyuki Morino, Hideshi Kawakami, Masayasu Matsumoto, Hirofumi Maruyama
Mutations in optineurin (OPTN) have been identified in a small proportion of sporadic and familial amyotrophic lateral sclerosis (ALS) cases. Recent evidences suggest that OPTN would be involved in not only the pathophysiological mechanisms of motor neuron death of ALS but also myofiber degeneration of sporadic inclusion body myositis. However, the detailed role of OPTN in muscle remains unclear. Initially, we showed that OPTN expression levels were significantly increased in the denervated muscles of mice, suggesting that OPTN may be involved in muscle homeostasis...
January 2022: Differentiation; Research in Biological Diversity
https://read.qxmd.com/read/34272080/a-recessive-s174x-mutation-in-optineurin-causes-amyotrophic-lateral-sclerosis-through-a-loss-of-function-via-allele-specific-nonsense-mediated-decay
#28
JOURNAL ARTICLE
Marc Gotkine, Martina de Majo, Chun Hao Wong, Simon D Topp, Rachel Michaelson-Cohen, Silvina Epsztejn-Litman, Rachel Eiges, Yossef Lerner Y, Moein Kanaan, Hagar Mor Shaked, Nada Alahmady, Caroline Vance, Stephen J Newhouse, Gerome Breen, Agnes L Nishimura, Christopher E Shaw, Bradley N Smith
Loss of function (LoF) mutations in Optineurin can cause recessive amyotrophic lateral sclerosis (ALS) with some heterozygous LoF mutations associated with dominant ALS. The molecular mechanisms underlying the variable inheritance pattern associated with OPTN mutations have remained elusive. We identified that affected members of a consanguineous Middle Eastern ALS kindred possessed a novel homozygous p.S174X OPTN mutation. Analysis of these primary fibroblast lines from family members identified that the p...
October 2021: Neurobiology of Aging
https://read.qxmd.com/read/34258561/the-optineurin-tia1-pathway-inhibits-aberrant-stress-granule-formation-and-reduces-ubiquitinated-tdp-43
#29
JOURNAL ARTICLE
Taichi Kakihana, Masahiko Takahashi, Yoshinori Katsuragi, Shun-Ichi Yamashita, Junya Sango, Tomotake Kanki, Osamu Onodera, Masahiro Fujii
Amyotrophic lateral sclerosis (ALS) is a degenerative motor neuron disease characterized by the formation of cytoplasmic ubiquitinated TDP-43 protein aggregates in motor neurons. Stress granules (SGs) are stress-induced cytoplasmic protein aggregates containing various neuropathogenic proteins, including TDP-43. Several studies have suggested that SGs are the initial site of the formation of pathogenic ubiquitinated TDP-43 aggregates in ALS neurons. Mutations in the optineurin ( OPTN ) and TIA1 genes are causative factors of familial ALS with TDP-43 aggregation pathology...
July 23, 2021: IScience
https://read.qxmd.com/read/34099552/als-and-ftd-associated-missense-mutations-in-tbk1-differentially-disrupt-mitophagy
#30
JOURNAL ARTICLE
Olivia Harding, Chantell S Evans, Junqiang Ye, Jonah Cheung, Tom Maniatis, Erika L F Holzbaur
TANK-binding kinase 1 (TBK1) is a multifunctional kinase with an essential role in mitophagy, the selective clearance of damaged mitochondria. More than 90 distinct mutations in TBK1 are linked to amyotrophic lateral sclerosis (ALS) and fronto-temporal dementia, including missense mutations that disrupt the abilities of TBK1 to dimerize, associate with the mitophagy receptor optineurin (OPTN), autoactivate, or catalyze phosphorylation. We investigated how ALS-associated mutations in TBK1 affect Parkin-dependent mitophagy using imaging to dissect the molecular mechanisms involved in clearing damaged mitochondria...
June 15, 2021: Proceedings of the National Academy of Sciences of the United States of America
https://read.qxmd.com/read/34093394/novel-optineurin-frameshift-insertion-in-a-family-with-frontotemporal-dementia-and-parkinsonism-without-amyotrophic-lateral-sclerosis
#31
JOURNAL ARTICLE
Jacqueline Dominguez, Jeryl Tan Yu, Yi Jayne Tan, Arlene Ng, Ma Fe De Guzman, Boots Natividad, Ma Luisa Daroy, Jemellee Cano, Justine Yu, Michelle M Lian, Li Zeng, Weng Khong Lim, Jia Nee Foo, Adeline S L Ng
Frontotemporal Dementia (FTD) is a common cause of Young Onset Dementia and has diverse clinical manifestations involving behavior, executive function, language and motor function, including parkinsonism. Up to 50% of FTD patients report a positive family history, supporting a strong genetic basis, particularly in cases with both FTD and amyotrophic lateral sclerosis (FTD-ALS). Mutations in three genes are associated with the majority of familial FTD (fFTD) cases - microtubule associated protein tau gene ( MAPT ), granulin precursor ( GRN ), and hexanucleotide repeat expansions in chromosome 9 open reading frame 72- SMCR8complex subunit (C9orf72) while mutations in other genes such as optineurin ( OPTN ) have rarely been reported...
2021: Frontiers in Neurology
https://read.qxmd.com/read/34025336/mutation-screening-of-the-gle1-gene-in-a-large-chinese-cohort-of-amyotrophic-lateral-sclerosis-patients
#32
JOURNAL ARTICLE
Yanran Li, Bo Sun, Zhanjun Wang, Zhengqing He, Fei Yang, Hongfen Wang, Fang Cui, Zhaohui Chen, Li Ling, Chaodong Wang, Xusheng Huang
Amyotrophic lateral sclerosis (ALS) is a fatal progressive neurodegenerative disease involving the upper and lower motor neurons of the spinal cord, brainstem, and cerebral cortex. At least 30 genes have been implicated in familial ALS (fALS) and sporadic ALS (sALS). Kaneb et al. (2015) first carried out a large-scale sequencing study in ALS patients and identified two loss-of-function (LOF) variants in the GLE1 gene. The LOF mutation-induced disruption of RNA metabolism through the haploinsufficiency mechanism is implicated in ALS pathogenesis...
2021: Frontiers in Neuroscience
https://read.qxmd.com/read/34023378/human-primary-retinal-cells-as-an-in-vitro-model-for-investigating-defective-signalling-caused-by-optn-mutants-associated-with-glaucoma
#33
JOURNAL ARTICLE
Zuberwasim Sayyad, Sushma Vishwakarma, Tarjani Vivek Dave, Milind N Naik, Vegesna Radha, Inderjeet Kaur, Ghanshyam Swarup
Studies carried out on the pathogenesis of glaucoma using murine cell lines and animal models require to be validated in human cells. Therefore, we explored the possibility of using human primary retinal cells (hPRCs) in culture as a model for molecular studies and testing of potential therapeutic drugs. For this purpose, central retinal tissue, obtained from the enucleated eyes of patients with anterior staphyloma, was digested with trypsin and grown in a medium containing supplements (basic fibroblast growth factor and fetal bovine serum)...
September 2021: Neurochemistry International
https://read.qxmd.com/read/33951500/conformational-stabilization-of-optineurin-by-the-dynamic-interaction-of-linear-polyubiquitin
#34
JOURNAL ARTICLE
Akira Kitamura, Rika Numazawa, Masataka Kinjo
Optineurin produces intracellular multi-functions involving autophagy, vesicular trafficking, and negative regulation of inflammation signaling through interaction with various proteins such as ATG8/LC3, Rab8, and polyubiquitin. Optineurin is a component of cytoplasmic inclusion bodies (IBs) in motor neurons from amyotrophic lateral sclerosis (ALS), and its mutation E478G, has been identified in patients with ALS. However, the mechanism by which polyubiquitin binding modulates the interaction partners of OPTN and ALS-associated IB formation is still unclear...
June 25, 2021: Biochemical and Biophysical Research Communications
https://read.qxmd.com/read/33723228/the-e50k-optineurin-mutation-impacts-autophagy-mediated-degradation-of-tdp-43-and-leads-to-rgc-apoptosis-in-vivo-and-in-vitro
#35
JOURNAL ARTICLE
Shiqi Zhang, Zhengbo Shao, Xinna Liu, Mingying Hou, Fang Cheng, Dawei Lei, Huiping Yuan
The glaucoma-associated E50K mutation in optineurin (OPTN) is known to affect autophagy and cause the apoptosis of retinal ganglion cells (RGCs), but the pathogenic mechanism remains unclear. In this study, we investigated whether the OPTN (E50K) mutation caused TDP-43 aggregation by disrupting autophagy in vivo and in vitro. OPTN (E50K) mutant mice were generated and analysed for genotype and phenotype. Adeno-associated virus type 2 vectors containing either GFP only, GFP-tagged wild-type OPTN or GFP-tagged E50K-mutated OPTN were used to transfect R28 cells...
March 15, 2021: Cell Death Discovery
https://read.qxmd.com/read/33606761/amyotrophic-lateral-sclerosis-als-prediction-model-derived-from-plasma-and-csf-biomarkers
#36
JOURNAL ARTICLE
Radhika Khosla, Manjari Rain, Suresh Sharma, Akshay Anand
Amyotrophic Lateral Sclerosis (ALS) is a degenerative disorder of motor neurons which leads to complete loss of movement in patients. The only FDA approved drug Riluzole provides only symptomatic relief to patients. Early Diagnosis of the disease warrants the importance of diagnostic and prognostic models for predicting disease and disease progression respectively. In the present study we represent the predictive statistical model for ALS using plasma and CSF biomarkers. Forward stepwise (Binary likelihood) Logistic regression model is developed for prediction of ALS...
2021: PloS One
https://read.qxmd.com/read/33548116/a-glaucoma-and-als-associated-mutant-of-optn-induces-neuronal-cell-death-dependent-on-tbk1-activity-autophagy-and-er-stress
#37
JOURNAL ARTICLE
Swetha Medchalmi, Priyanka Tare, Zuberwasim Sayyad, Ghanshyam Swarup
Mutations in OPTN are associated with glaucoma, an eye disease, and also with amyotrophic lateral sclerosis (ALS), a motor neuron disease. A 2-bp insertion in OPTN (691_692insAG or 2bpIns-OPTN) is associated with both glaucoma and ALS. This mutation results in frame shift after 127 amino acids, giving rise to a protein with C-terminal aberrant sequence. We have explored the mechanism of induction of cell death by this mutant in a motor neuron cell line, NSC-34, and also in a retinal cell line, 661W. Compared to wild-type OPTN, this mutant induced more cell death in NSC-34 and 661W cells...
August 2021: FEBS Journal
https://read.qxmd.com/read/33296728/optineurin-defects-cause-tdp43-pathology-with-autophagic-vacuolar-formation
#38
JOURNAL ARTICLE
Takashi Kurashige, Masahito Kuramochi, Ryosuke Ohsawa, Yui Yamashita, Go Shioi, Hiroyuki Morino, Masaki Kamada, Takashi Ayaki, Hidefumi Ito, Yusuke Sotomaru, Hirofumi Maruyama, Hideshi Kawakami
We previously showed that optineurin (OPTN) mutations lead to the development of amyotrophic lateral sclerosis. The association between OPTN mutations and the pathogenesis of amyotrophic lateral sclerosis remains unclear. To investigate the mechanism underlying its pathogenesis, we generated Optn knockout mice. We evaluated histopathological observations of these mice and compared with those of OPTN- amyotrophic lateral sclerosis cases to investigate the mechanism underlying the pathogenesis of amyotrophic lateral sclerosis caused by OPTN mutations...
January 2021: Neurobiology of Disease
https://read.qxmd.com/read/33214085/corrigendum-to-respiratory-pathology-in-the-optn-mouse-model-of-amyotrophic-lateral-sclerosis-respir-physiol-neurobiol-282-2020-103525
#39
Angela L McCall, Justin S Dhindsa, Logan A Pucci, Amanda F Khan, Anna F Fusco, Debolina D Biswas, Laura M Strickland, Henry C Tseng, Mai K ElMallah
No abstract text is available yet for this article.
November 16, 2020: Respiratory Physiology & Neurobiology
https://read.qxmd.com/read/33145792/multisystem-proteinopathy-where-myopathy-and-motor-neuron-disease-converge
#40
REVIEW
Manisha K Korb, Virginia E Kimonis, Tahseen Mozaffar
Multisystem proteinopathy (MSP) is a pleiotropic group of inherited disorders that cause neurodegeneration, myopathy, and bone disease, and share common pathophysiology. Originally referred to as inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia (IBMPFD), attributed to mutations in the gene encoding valosin-containing protein (VCP), it has more recently been discovered that there are several other genes responsible for similar clinical and pathological phenotypes with muscle, brain, nerve, and bone involvement, in various combinations...
April 2021: Muscle & Nerve
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